Summary: The most popular replacement heart valve designs (so called ?bioprosthetic heart valves? or BHV) continue to be fabricated from xenograft biomaterials for both current and novel valve designs (e.g. standard stented valve, percutaneous delivery). Failure continues to be the result of leaflet structural deterioration mediated by fatigue and/or tissue mineralization, with durability limited to 10-15 years. Such limitations results from a combination of valve design and the intrinsic fatigue response of the constituent xenograft biomaterials. Thus, improved durability remains an important clinical goal and represents a unique cardiovascular engineering challenge resulting from the extreme valvular mechanical demands that occur with blood contact. Yet, current BHV assessment relies exclusively on device-level evaluations, which are confounded by simultaneous and highly coupled biomaterial mechanical behaviors and fatigue, valve design, hemodynamics, and calcification. Thus, despite decades of clinical BHV usage and growing popularity, there exists no acceptable method for simulating replacement valve function and durability at both the device and component biomaterial levels. This situation has contributed to the current stagnation in BHV development, limiting rationally developed improvements in prosthetic heart valve durability. We thus hypothesize that with the use of advanced biosolid mechanics simulations of the fatigue response of xenograft biomaterials coupled to state-of-the-art fluid-structure interaction (FSI) methods, a biomechanically rigorous and physiologically realistic approach to predict BHV performance can be developed. We will develop these coupled computational goals first in parallel, then combine and validate them in a final project stage.